We find that the SH2-containing Inositol Phosphatase (SHIP) plays a crucial role in defining the inhibitory repertoire of NK cells in vivo. Four key findings made by our group support this hypothesis: (1) SHIP is recruited to both Ly49A and Ly49C in vivo, (2) the 85kD regulatory subunit of P1-3-Kinase (P13K) is recruited to Ly49A in vivo, (3) Akt is constitutively active in SHIP-/- NK cells in vivo and (4) a subset of NK cells that co express Ly49A and Ly49C dominates the adult NK compartment in SHIP-/- mice. Ly49A and Ly49C can interact with self MHC ligands in our SHIP-/- mice, but also ligands of other MHC haplotypes. This promiscuous NK inhibitory repertoire has profound functional consequences as SHIP-/- mice fail to reject fully histo-incompatible marrow grafts. Strikingly, we find that survival of SHIP-/- mice is dramatically enhanced relative to wild-type littermates following transplantation of fully histo-incompatible marrow. These findings demonstrate a critical role for SHIP in two processes that limit the success of histo-incompatible marrow transplantation: graft rejection and graft-vs.-host disease. We now propose to confirm and extend our initial observations to gain a better understanding of how SHIP shapes the NK cell inhibitory repertoire and to better understand how this impacts marrow transplantation across major histocompatibility barriers. Specifically we will: (1) Determine the mechanism by which SHIP influences the NK inhibitory repertoire, (2) Determine whether a "self-restricted" NK inhibitory repertoire alters the ability of NK cells to respond to activating receptors and (3) Determine the mechanism for failure of graft rejection and abrogated GVHD during allogeneic BMT in SH1P-/- mice.